The presented protocol describes an investigation strategy and systematic review to evaluate the clinical effectiveness and safety of Shugan Jieyu capsules for treating insomnia.
A systematic review and meta-analysis were conducted to evaluate the clinical effectiveness and safety of Shugan Jieyu capsules for treating insomnia by searching seven databases up to February 21, 2022. The study was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The quality of the studies was assessed using the risk of bias assessment tool. This article describes in detail how to retrieve and screen the literature. The detailed steps for conducting the meta-analysis are also included in the protocol. Fourteen studies were found to be eligible, including 1,283 insomnia patients (644 with and 639 without Shugan Jieyu capsules at baseline). The meta-analysis showed a better total clinical effectiveness (odds ratio [OR]: 5.71, 95% confidence interval [CI]: 3.56 to 9.15) and a lower Pittsburgh Sleep Quality Index (PSQI) score (mean difference [MD]: −2.95, 95% CI: −4.97 to −0.93) with combined Shugan Jieyu capsules and Western medicine compared to Western medicine alone. The secondary outcomes showed that the Shugan Jieyu capsule group had significantly reduced adverse reactions and improvements in sleep duration, night awakening, nightmares with excessive dreaming, daytime sleepiness, and low energy. Further multicenter randomized trials must be encouraged to provide more concrete evidence on whether Shugan Jieyu capsules are beneficial in routine clinical practice.
Insomnia is a sleep disorder characterized by difficulty in falling asleep, difficulty in maintaining sleep, and premature or intermittent waking1, which can cause discomfort and disrupt daily functioning. According to the China Sleep Study Report (2022), over 300 million Chinese people suffered from sleep disorders in 2021, with a prevalence of insomnia among adults as high as 38.2%2.
Western medicine for insomnia treatment typically involves psychological therapies or medication3. Psychotherapies, such as simple insomnia behavior therapy and cognitive insomnia behavior therapy, aim to modify the behaviors that contribute to sleep difficulties. Sedative-hypnotic drugs, which act quickly to induce sleep, are also commonly used to treat insomnia4. However, these drugs can have toxic side effects, including respiratory depression, hypotension, and excessive sedation. The prolonged usage of these drugs can lead to dependence, resulting in significant harm and burden to the patients and their families5,6,7. In traditional Chinese medicine (TCM), insomnia is referred to as "no sleep" or "sleeplessness" and is believed to result from deficiencies in organs such as the liver, kidneys, spleen, and heart, as well as dysfunction of the heart and mind8. In the history of traditional Chinese medicine, several experts have described the mechanisms underlying insomnia; specifically, insomnia is thought to occur due to disorder of the function of the internal organs, the loss of harmony between the qi and blood, and the disorder of yin and yang, which lead to a loss of nourishment or the disturbance of the heart and mind. The basic pathological alternation of insomnia is the loss of yang and yin9. Utilizing the active ingredients of TCM and following the principles of TCM compounding for complex conditions, research10,11,12,13 has shown that TCM plays a critical role in preventing and treating insomnia. One example of a TCM treatment for insomnia is the Shugan Jieyu capsule14, which comprises Hypericumperforatum L15,16 and Acanthopanax senticosus17.
Acanthopanax senticosus18,19, a traditional Chinese herb, has been used for tonifying the middle qi and kidney and calming the mind. It has been found to effectively improve symptoms such as insomnia, excessive dreaming, and neurasthenia. Hypericum perforatum20, another traditional Chinese herb, has demonstrated antidepressant properties, with its active components potentially possessing similar antidepressant effects to tricyclic antidepressants (TCAS) and selective serotonin reuptake inhibitors (SSRIs), but with better tolerability. The combination of Hypericum perforatum and Acanthopanax senticosus has been found to regulate neurotransmitters, improve neuronal synaptic plasticity, and clinically relieve insomnia caused by mental illness; indeed, it improves the sleep quality and cognitive function of patients with liver-depression type insomnia21,22. Syndrome differentiation is a unique characteristic of TCM. The Shugan Jieyu capsule containing Hypericum perforatum and Acanthopanax senticosus is formulated to treat insomnia caused by stagnation of liver qi. It has been reported to be effective in improving the condition and safety of patients21,22. Combining these two herbs has been proven to relieve depression, calm the mind, soothe the liver, and strengthen the spleen23,24,25. However, there currently needs to be more conclusive evidence regarding the clinical effectiveness and safety of Shugan Jieyu capsules in treating insomnia.
There are various forms of Chinese herbal medicine for treating insomnia, including decoction, patent medicine, plaster, and auricular point sticking26. Previous research has examined the effect of traditional Chinese herbs on insomnia using meta-analyses. It has been found that traditional Chinese herbs significantly improve the symptoms of patients with primary insomnia, are superior to placebo, and have promising potential for research and development27,28. This study aims to evaluate the clinical effectiveness and safety of the Shugan Jieyu capsule in treating insomnia through a systematic evaluation and meta-analysis in order to provide clinical evidence and guidance for using these capsules.
The inclusion criteria for this study were defined using the population, intervention or exposure, comparison, outcome(s) (PICO) framework29. The inclusion criteria for this study were as follows: (1) randomized controlled trials (RCTs) or semi-RCTs that enrolled patients diagnosed with insomnia30; (2) studies in which the experimental group received Western medicine in combination with Shugan Jieyu capsules, while the control group received Western medicine alone (Western medicines include alprazolam tablets31, risperidone32, estazolam tablets33, aripiprazole orally disintegrating tablets34, mirtazapine35, escitalopram oxalate tablets36, eszopiclone tablets37, zopiclone tablets38, and fluoxetine dispersible tablets39); (3) studies published in Chinese or English; (4) studies in which the primary outcomes were the overall clinical effectiveness and the Pittsburgh Sleep Quality Index (PSQI)40. According to the "Diagnostic Effectiveness Criteria for Chinese Medicine Evidence"41 and the "Guidelines for Clinical Research on New Chinese Medicines"42, effective clinical outcomes are defined as patients being clinically documented as cured or showing efficacious results. The secondary outcomes identified include sleep latency, sleep duration, nighttime awakening, nightmares with excessive dreaming, daytime sleepiness, lack of energy, and sleep quality, all evaluated by the PSQI scale and the frequency of adverse events. Among these outcome measures, sleep latency, sleep duration, nighttime awakening, nightmares, daytime sleepiness, lack of energy, and sleep quality are all evaluated using the PSQI scale43.
The exclusion criteria were defined according to the PICO framework. The exclusion criteria for this study were as follows: (1) studies unrelated to insomnia; (2) duplicate published research; (3) non-randomized controlled trials; (4) non-clinical patient studies, such as preclinical and animal model studies; and (5) case reports, comments, conferences, reviews, and dissertations.
1. Software installation
2. Literature search and screening
3. Data extraction
4. Risk of bias assessment and quality of evidence
5. Meta-analysis
Search results
A total of 1,117 studies were identified from databases, including 204 in Chinese and 913 in English. After eliminating 392 duplicates, 725 studies remained. After reading the titles and abstracts, 31 studies remained. Eventually, 14 studies were included through reading the full texts. The search process and selection procedure are shown in Figure 1.
Study characteristics
The characteristics of the included studies are provided in Table 1. The 14 studies involved 1,283 patients with insomnia (644 treated with and 639 treated without Shugan Jieyu capsules), including 445 females (35%), 528 males (41%), and 310 patients of unknown gender. The patients ranged in age from 18 to 74 years, with an average of 46 years. There were no statistically significant baseline differences in patient gender, age, or basic disease between the experimental and control groups in the 14 studies. All the randomized controlled trials (RCTs) were conducted in China.
Methodological quality
The methodological quality assessment results of the 14 studies are shown in Figure 1 and Figure 2. Five trials reported specific randomization methods (random number table)48,49,50,51,52 and, thus, were assessed as low risk. One trial53 was judged as high risk, using the order of consultation, and other trials mentioned randomization but no specific methods. None of the trials reported minute details of allocation concealment and blinding of the outcome assessment. None of the studies used placebo, and blinding appeared unlikely to be implemented, so the risk of participant bias and lack of personnel blinding was considered high. In all the studies, the risk of incomplete outcome reporting was lower. For five25,50,53,54,55 studies, it was difficult to determine whether there was a risk of selective reporting. Two studies47,48 had unclear risks due to incomplete baseline measurements.
Primary outcomes
Nine studies24,49,50,51,52,54,56,57,58, including 866 patients, reported the total number of clinically effective cases. The total clinical effectiveness rate was 94% (406/433) in the experimental group compared to 73% (317/433) in the control group. Compared with the control group, the total clinical effectiveness was significantly higher in the experimental group (OR: 5.71, 95% CI: 3.56 to 9.15, I2 = 0%) (Figure 3). Eight studies stated that the experimental group showed reduced overall PSQI scores compared to the control group, and one study reported opposite results25. After pooling the data, the mean difference (MD) was −2.95 (95% CI: −4.97 to −0.93, I2= 97%) (Figure 4).
Secondary outcomes
Eight studies24,48,49,52,53,56,57,58, including 717 patients, reported a number of adverse events. The adverse reaction rate was 13% (45/358) in the experimental group compared to 21% (74/359) in the control group. The experimental group had significantly fewer adverse reactions (OR: 0.56, 95% CI: 0.32 to 0.97, I2 = 35%) (Figure 5). The experimental group did not show a significant reduction in sleep latency (MD: −0.26, 95% CI: −1.32 to 0.80, I2 = 96%) (Figure 6). Four studies49,50,52,55, including 392 patients, reported the sleep duration. Three studies showed that the experimental group showed statistically significant improvements in sleep duration, and one study reported that the experimental group did not differ significantly from the control group in terms of sleep duration52. After pooling the data, the MD was 1.06 (95% CI: 0.11 to 2.01, I2 = 91%) (Figure 7).
In comparison with the control group, the experimental group was associated with a significant decrease of −0.46 in night awakening (95% CI: −0.57 to −0.35, I2 = 0%), of −0.48 in nightmares with excessive dreaming (95% CI: −0.56 to −0.39, I2 = 0%), of −0.40 in daytime sleepiness (95% CI: −0.69 to −0.10, I2 = 87%), and of −0.41 in low energy (95% CI: −0.54 to −0.29, I2 = 0%) (Figure 8, Figure 9, Figure 10, Figure 11). Additionally, the experimental group showed significantly improved sleep quality (MD: −0.78, 95% CI: −1.54 to −0.02, I2 = 90%) (Figure 12).
Quality of evidence
The results of the GRADE46 evaluation on the studies examining the effectiveness and safety of Chinese medicine Shugan Jieyu capsules for insomnia treatment showed that the evidence qualities were medium, low, or very low. The details can be found in Supplementary Table 1.
Figure 1: Assessment of the risk of bias according to the authors' judgment. This graph represents the percentages of respective bias across all the included literature. Please click here to view a larger version of this figure.
Figure 2: Risk of bias summary. The specific biases identified for each study included in the analysis. The red, yellow, and green circles represent high, unclear, and low risk of bias, respectively. For further details, please see Table 1. Please click here to view a larger version of this figure.
Figure 3: Forest plot for the pooled analysis of the total clinical effectiveness. Please click here to view a larger version of this figure.
Figure 4: Forest plot for the pooled analysis of the PSQI total score. Abbreviation: SD = standard deviation. Please click here to view a larger version of this figure.
Figure 5: Forest plot for the pooled analysis of the improvement of adverse reactions. Please click here to view a larger version of this figure.
Figure 6: Forest plot for the pooled analysis of sleep latency improvement. Abbreviation: SD = standard deviation. Please click here to view a larger version of this figure.
Figure 7: Forest plot for the pooled analysis of sleep duration improvement. Abbreviation: SD = standard deviation. Please click here to view a larger version of this figure.
Figure 8: Forest plot for the pooled analysis of night awakening. Abbreviation: SD = standard deviation. Please click here to view a larger version of this figure.
Figure 9: Forest plot for the pooled analysis of nightmares with excessive dreaming. Abbreviation: SD = standard deviation. Please click here to view a larger version of this figure.
Figure 10: Forest plot for the pooled analysis of daytime sleepiness. Abbreviation: SD = standard deviation. Please click here to view a larger version of this figure.
Figure 11: Forest plot for the pooled analysis of low energy. Abbreviation: SD = standard deviation. Please click here to view a larger version of this figure.
Figure 12: Forest plot for the pooled analysis of sleep quality. Abbreviation: SD = standard deviation. Please click here to view a larger version of this figure.
Table 1: Basic information of the included studies. *: (1) Total clinical efficiency; (2) PSQI overall score; (3) Adverse reactions; (4) Sleep latency; (5) Sleep duration; (6) Night awakening; (7) Nightmares with excessive dreaming; (8) Daytime sleepiness; (9) Low energy; (10) Sleep quality. Abbreviations: T = experimental group; C = control group; "-" = not mentioned. Please click here to download this Table.
Supplementary Figure 1: Handling the PubMed database. (A) The main window of the literature search in Pubmed. (B) The main window for downloading all the retrieved literature in Pubmed. Please click here to download this File.
Supplementary Figure 2: Working in Endnote. (A) The main window for importing the retrieved literature in Endnote. (B) The main window for creating the inclusion and exclusion groups in Endnote. (C) The main window for removing duplicates in Endnote. Please click here to download this File.
Supplementary Figure 3: Adding research to RevMan. (A) The main window for creating a new file in RevMan. (B) The main window for adding the included literature in RevMan. (C) The main window for entering the quality evaluation results in RevMan. Please click here to download this File.
Supplementary Figure 4: Literature quality evaluation in RevMan. (A) The main window for creating a graph of RoB in RevMan. (B) The main window for adding the outcome indicators in RevMan. Please click here to download this File.
Supplementary Figure 5: Meta-analysis. (A) The main window for adding the study data in RevMan. (B) The main window for creating forest plots in RevMan. Please click here to download this File.
Supplementary Table 1: GRADE evidence profile. 1, downgrade one level: the quality of included literature is low; 2, downgrade one level: heterogeneity in the data synthesis results, I2 > 50%; 3, downgrade one level: the confidence interval is too wide; 4, downgrade one level: the sample size is too small. Abbreviations: MD = mean difference; OR = odds ratio; CI = confidence interval. *: the overall quality of the evidence. Please click here to download this File.
Supplementary File 1: The details of the retrieval strategy for this study. Please click here to download this File.
Supplementary File 2: PRISMA checklist. Overall, 1,117 articles were identified initially through the literature search, and 14 full-text articles were reviewed and entered into the final analysis. Please click here to download this File.
In the present study, a comprehensive evaluation of the effectiveness and safety of Shugan Jieyu capsules for treating insomnia was conducted, and the following results were observed. In the experimental group, using Shugan Jieyu capsules in combination with conventional Western medicine improved the overall clinical effectiveness for patients with insomnia and resulted in higher PSQI scores. Additionally, the Shugan Jieyu capsules group showed improvements in clinical outcomes, such as sleep latency, night awakening, nightmares, daytime sleepiness, lack of energy, and sleep quality compared to the control group.
Previous research has demonstrated that Hypericumperforatum L can inhibit the reuptake of central neurotransmitters such as 5-hydroxytryptamine, dopamine, and norepinephrine, thereby increasing the concentration of neurotransmitters in the synapse and producing antidepressant and anxiolytic effects59. Acanthopanax senticosus, on the other hand, has been shown to improve the blood flow to the heart and brain, regulate the function of the central nervous and endocrine systems, and increase the viability of neurons60, thus producing calming, fatigue-reducing, and immune-boosting effects. Since Shugan Jieyu capsules are mainly composed of these two ingredients, they may be effective in treating insomnia61.
In terms of safety, the use of Shugan Jieyu capsules resulted in significantly fewer clinical adverse reactions in the treatment of insomnia compared to the use of Western medicine alone (including alprazolam tablets, risperidone, dexzopiclone tablets, aripiprazole orally disintegrating tablets, mirtazapine, escitalopram oxalate tablets, eszopiclone tablets, zopiclone tablets, and fluoxetine dispersible tablets) in the control group. A previous study by Shi et al.62 found that the combination of Shugan Jieyu capsules and non-benzodiazepines (NBZDs) was associated with improved clinical effectiveness and PSQI scores compared to NBZDs alone for the adjunctive treatment of insomnia, but their study did not report any findings on safety. A study by Wang et al.63 on using Shumian capsules for insomnia found that while the clinical effectiveness was not significantly improved compared to Western medicine, the capsules demonstrated better safety compared to Western medicine. The results of the present meta-analysis suggest that using Shugan Jieyu capsules has higher effectiveness than Western medicine alone. Still, due to the low quality of the literature, high-quality clinical studies are needed to fully explore and compare the clinical effectiveness and safety of these two treatments.
Meta-analysis is a statistical method used to compare and synthesize the results of studies on a particular clinical scientific problem, and meta-analyses are often utilized in systematic reviews to perform a quantitative pooled analysis. The reliability of the conclusions drawn is dependent on the quality of the included studies, making the formulation of appropriate inclusion and exclusion criteria and retrieval strategies according to the PICO framework crucial. Any retrieval bias or omission in the literature can lead to significant information bias in the meta-analysis results.
Before combining the effect sizes, a meta-analysis should test for heterogeneity. When the heterogeneity is considerable, the results of the meta-analysis may be less reliable, and techniques such as random-effects models, subgroup analysis, and meta-regression should be used to correct the results, compare the combined effects before and after the correction, or remove the low-quality literature before re-running the meta-analysis64. However, these correction methods do not guarantee the elimination of heterogeneity, as this study still showed high levels of heterogeneity after both using random-effects models and removing low-quality literature. Further investigation into better methods for addressing heterogeneity is necessary.
The combination of Shugan Jieyu capsules with Western medicine appears to improve clinical symptoms and the overall effectiveness rate for insomnia patients to a certain extent while reducing the side effects. Further multicenter randomized trials examining clinical endpoints are needed to provide evidence on the usefulness of Shugan Jieyu capsules in routine clinical practice.
Limitations
Several limitations exist in this meta-analysis, which must be considered. Above all, the methodological quality of the studies was poor. None of the trials reported specific details of allocation concealment, blinding of the outcome assessment, and blinding of the participants and personnel. Secondly, some of the outcome measures were evaluated using the PSQI scale, and the data in the evaluation form were from patients' subjective self-assessment, so there may have been cases of patients filling the forms incorrectly or deviation between subjective evaluations and the actual situation, which would affect the quality of the evaluation. In addition, selection bias may exist because no trials showed negative results in the included studies. Thus, the effectiveness of Shugan Jieyu capsules for promoting insomnia might be overestimated. Meanwhile, insomnia patients often also experience depression, schizophrenia, perimenopausal syndrome, etc. The heterogeneity of the patients' accompanying diseases may affect the accuracy of the results. Moreover, subgroup analysis65 could not be performed, as it was not possible to collect the clinical outcomes of patients with different syndromes separately from the included literature. Finally, most studies had small sample sizes and short-term follow-ups, so further trials with high-quality, large sample sizes and long-term follow-ups are recommended to generate high-quality clinical evidence.
The authors have nothing to disclose.
This work was supported by the National Nature Foundation of China (grant number 82004504) and the Chinese Medicine Administration of Sichuan Province (grant number 2021MS199).
Endnote | Clarivate | Free trial version | EndNote is a widely used reference management tool to help you collect, organize, and share your references. Official website: https://endnote.com/downloads |
Microsoft Excel | Microsoft | Official Version | Microsoft Excel, a spreadsheet software with an intuitive interface, excellent computing capabilities and charting tools, is one of the most popular data processing software for personal computers. |
Microsoft Word | Microsoft | Official Version | Microsoft Word offers a number of easy-to-use document creation tools, as well as a rich set of features for creating complex documents, as well as text formatting or image manipulation. |
Revman | Cochrane collaboration | Official Version | Review Manager (RevMan) is the international Cochrane Collaboration's proprietary software for systematic reviewers to produce and maintain Cochrane systematic reviews. Official website: https://training.cochrane.org/online-learning/core-software-cochrane-reviews/revman/revman-5-download/download-and-installation |
Database websites | |||
CBM | http://www.sinomed.ac.cn/ | ||
CNKI | https://www.cnki.net/ | ||
Cochrane Library | https://www.cochranelibrary.com/ | ||
Embase | https://www.embase.com/ | ||
Pubmed | https://pubmed.ncbi.nlm.nih.gov/ | ||
VIP | http://www.cqvip.com/ | ||
Wan fang | https://www.wanfangdata.com.cn/ | ||
Web of Science | http://www.webofscience.com/ |